Limb Girdle Muscular Dystrophy (LGMD)
Before the advent of genetic testing, a group of patients commonly sharing a progressive pattern of proximal greater than distal muscular weakness with either autosomal-recessive (LGMD2) or dominant (LGMD1) inheritance were termed limb-girdle muscular dystrophies.
Recent advances in molecular and genetic analyses have now identified a number of distinct genetic mutations in these patients. LGMD1 subtypes usually have later onset in adulthood. LGMD2 usually present during childhood or adolescence, although some may present in early adulthood. Many of the LGMD2 subtypes have been linked to gene defects causing abnormalities of the sarcolemmal-associated proteins, including sargoglycans (alpha-SG, gamma-SG, beta-SG, and delta-SG), dystroglycans, calpain-3, dysferlin, fukutin- related protein (FKRP), telethonin, and titin. The most common LGMD2 subtypes include sarcoglycanopa- thies, dysferlinopathies, calpainopathies, and FKRP deficiencies. The distribution and pattern of weakness at onset most often affects the pelvic or shoulder girdle musculature or both. The rate of progression is slower than DMD (60,61,62). Clinical features of the most common forms of LGMD2 are shown in Table 12.2.Sarcoglycanopathies (LGMD 2C-2F)
Disruption of the sarcolemmal membrane cytoskeleton is a common feature of the sarcoglycanopathies. Most of the primary sargoglycan abnormalities lead to secondary deficiencies of alpha-sarcoglycan. Diagnosis of sarcoglycanopathies may be made with molecular genetic studies and immunohistochemical analysis of muscle biopsies. The age of onset of sarcoglycanopa- thies ranges from 2 to 15 years. Progression is variable with both more severe and milder phenotypes. Loss of ambulation may vary from 10 years to young adulthood. Weakness involves proximal greater than distal musculature. Calf pseudohypertrophy scapular winging, progressive contractures, and scoliosis often occur (61).
A dilated cardiomypathy may occur, particularly in alpha-SG and delta-SG. Intelligence is often normal.Dysferlinopathies (LGMD 2B)
Dysferlin is a skeletal muscle protein localized in the muscle cell membrane (63). It is involved in muscle contraction and contains C2 domains that play a role in calcium-mediated membrane fusion events, suggesting that it may be involved in membrane regeneration and repair. Specific mutations in this gene have been shown to cause autosomal-recessive limb girdle muscular dystrophy type 2B (LGMD2B) with proximal muscle involvement as well as Miyoshi myopathy, which presents with distal weakness involving the distal legs, including the gastrocnemius and soleus muscles (61). In LGMD 2B, no specific genotype-phenotype correlations have been established. LGMD 2B presents from 12 to 39 years, with early weakness of gastrocnemius, quadriceps and psoas muscles, and atrophy of the pelvic and shoulder girdle muscles. There is no scapular winging. Patients have difficulty tip-toeing and running. Weakness occurs in a distal lower extremity and/or pelvifemoral distribution. Progression is slow, with loss of ambulation 10 to 30 years after onset. Equinus contractures are common, and toe-walking may be a presenting sign. Respiratory and cardiac muscles are spared. Intelligence is normal.
Calpainopathies (LGMD 2A)
Heterogeneous dystrophies due to mutation of the cal- pain-3 gene are termed calpainopathy (62). Calpain-3 is
12.2
Characteristics of Autosomal Recessive Limb Girdle Muscular Dystrophies (LGMD)
| LGMD 2A | LGMD 2B | LGMD 2C | LGMD 2D | LGMD 2E | LGMD 2F | LGMD 2I | |||
| U.S. prevalence | 4,200 | 2,850 | 675 | 1,260 | 675 | 105 | 450 | ||
| Inheritance | AR | AR | XR | XR | AR | AR | XR | ||
| Gene location | 4p21 | 2p12-14 | 13q12 | 17q21 | 4q12 | 5q33 | 19q13.3 | ||
| Protein | Calpain-3 | Dysferlin | γ-sarcoglycan | γ-sarcoglycan (Adhalin) | γ -sarcoglycan | γ-sarcoglycan | Fukutin-related protein | ||
| Onset | Early: 30 years | 12-39 years Mean 19 ± 3 years | Mean 5 to 6 yrs C283Y mutation: arms | Weakness in gastrocnemius, quadriceps, and psoas Weakness in biceps after legs | Proximal > Distal Patchy distribution with some mutations Quadriceps: spared | Proximal > distal Symmetric quadriceps weakness | Proximal | Proximal Symmetric | Proximal > Distal Legs: Proximal Arms: proximal Face: mild weakness in older patients |
| Cardiac | No involvement | No involvement | Occasional; especially late in disease course | Dilated cardiomyopathy | Occasional cardiomyopathy | Dilated cardiomyopathy described; May occur without myopathy | Dilated cardiomyopathy in 30%-50% of patients |
| Respiratory | Rarely involved: PFTs rarely < 80% of normal | Rarely involved: | Functional vital capacity ranges from normal to severe | Functional vital capacity ranges from normal to severe | Variable respiratory involvement: | Variable respiratory involvement: | Variable respiratory involvement; some severe |
| Quality of life | Unknown | Unknown | Unknown | Unknown | Unknown | Unknown | Unknown |
| Muscle size | Limbs, pelvic and shoulder: Atrophy of posterior compartments | Hypertrophy: uncommon | Hypertrophy of calf and tongue in some patients | Calf hypertrophy in some patients | Prominent muscle hypertrophy | Calf hypertrophy Cramps | Calf, tongue and thigh hypertrophy Wasting in regions of weakness |
| Musculoskeletal | Contractures: calf (toe walking may be presenting sign) | Contractures: calf (toe walking may be presenting sign) | Lumbar hyperlordosis Scapular Winging | Scapular winging | Shoulders: scapular winging and muscle wasting | Scapular winging | Contractures in ankles (especially in non-ambulant) Scoliosis |
| CNS | Intelligence: Normal to mild mental retardation | No intellectual defect reported | No intellectual defect reported Hearing loss | No intellectual defect reported | No intellectual defect reported | No intellectual defect reported | No intellectual defect reported |
| Muscle pathology | Myopathic Necrosis and regeneration with fiber size variability Endomysial fibrosis Type I predominance with increasing weakness Normal Dystrophin and Sarcoglycan | Myopathic Necrosis and degeneration with variable fiber size ?Endomysial connective tissue Absent or dysferlin staining Normal Dystrophin and Sarcoglycan | Myopathic Inflammation: occasional Severe disease: absent γ-sarcoglycan Slowly progressive: Reduced γ-sarcoglycan Dystrophin: Normal or reduced | Myopathic Degeneration and regeneration Variable fiber size Endomysial connective tissue Myopathic grouping of fibers Absent or reduced adhalin γ-sarcoglycan | Myopathic Sarcoglycans: usually absent Dystrophin: often reduced, but not absent | Myopathic Fiber degeneration Fiber regeneration ?-Sarcoglycan absent Other sarcoglycans absent or reduced | Myopathic Necrosis and degeneration Variable fiber size connective tissue Type 1 fiber predominance staining for adhalin |
| Blood chemistry and hematology | CK: 7 to 80 times normal | CK: 10 to 72 times normal | CK: Very high | CK: Very high (often >5,000) | CK: Very high (often >5,000) | CK: 10 to 50 times normal | CK : Very high 1,000-8,000) |
AR-LGMD, autosomal recessive limb girdle muscular dystrophy.
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a nonlysosomal calcium-dependent proteinase specifically expressed in muscle.
Muscle biopsies reveal that calpainopathy patients have normal dystrophin and sarcoglycan labeling but lack calpain-3. An early-onset form occurs before 12 years of age and has the most severe progression. The “Leyden Mobius” subtype has an onset between 13 and 30 years. Others with later onset have been reported. Pelvic girdle weakness is present and symptomatic from the onset, but often with striking sparing of the hip abductors, even relatively late into the course of the disease. Scapular winging is usually present from the early stages. The rate of deterioration varies between families. Wheelchair dependency typically occurs at 10-30 years after the onset of symptoms. The disease is predominantly symmetrical and atrophic, with prominent calves seen in only a minority of cases. Achilles tendon contractures may be an early sign, and spine deformity may also develop. Respiratory, but not cardiac, complications have been reported.Fukutin-Related Protein
This dystrophy is caused by pathogenic mutations in the gene for fukutin-related protein (FKRP), which is involved in the glycosylation of cell surface molecules in muscle fibers (63). The majority of the LGMD 2I patients carry a common C826A missense mutation in the FKRP gene. In the LGMD 2I patients, different mutations in the FKRP gene are associated with several secondary muscle protein reductions, and the deficiencies of α2-laminin and α-DG on sections are prevalent, independent of the mutation type or the clinical severity. LGMD 2I has a relatively mild and variable course, with the age at onset varying from the first to the fourth or fifth decade of life. Progression is slow. Serum CK is elevated and intelligence is preserved, although structural brain changes have been reported.
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